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Subjects

Abstract

Humoral immune responses to microbial polysaccharide surface antigens can prevent bacterial infection but are typically strain specific and fail to mediate broad protection against different serotypes. Here we describe a panel of affinity-matured monoclonal human antibodies from peripheral blood immunoglobulin M–positive (IgM+) and IgA+ memory B cells and clonally related intestinal plasmablasts, directed against the lipopolysaccharide (LPS) O-antigen of Klebsiella pneumoniae, an opportunistic pathogen and major cause of antibiotic-resistant nosocomial infections. The antibodies showed distinct patterns of in vivo cross-specificity and protection against different clinically relevant K. pneumoniae serotypes. However, cross-specificity was not limited to K. pneumoniae, as K. pneumoniae–specific antibodies recognized diverse intestinal microbes and neutralized not only K. pneumoniae LPS but also non–K. pneumoniae LPS. Our data suggest that the recognition of minimal glycan epitopes abundantly expressed on microbial surfaces might serve as an efficient humoral immunological mechanism to control invading pathogens and the large diversity of the human microbiota with a limited set of cross-specific antibodies.

Vinogradov, E. et al. Structures of lipopolysaccharides from Klebsiella pneumoniae. Eluicidation of the structure of the linkage region between core and polysaccharide O chain and identification of the residues at the non-reducing termini of the O chains. J. Biol. Chem.277, 25070–25081 (2002).

Acknowledgements

We thank S. Kaluzewski (National Institute of Public Health–National Institute of Hygiene) for an unencapsulated mutant of a prototype O3:K55 strain 5505; S. Melegh (University of Pécs) for clinical isolates Kp2 (O3:K60) and Kp14 (O3:K35); A. Valverde (University Hospital Ramón y Cajal) for clinical isolate Kp81 (O3b:K non-typeable); A. Heidtmann, L. Kummer, B. Jocher and J. Braun for help with sample acquisition; C. Varga for performing animal experiments; C. Busse for help with experimental design; M. Nussenzweig (The Rockefeller University) for recombinant gp140 from strain YU2; and P. Sehr, R. Murugan, P. Thiele, C. Winter, D. Foster, A. Götze and the DKFZ High-Throughput Sequencing Unit of the Genomics and Proteomics Core Facility and the DKFZ and MPIIB Flow Cytometry Core Facilities for technical support. Supported by the European Funding Program Eurostars (E! 7563 – KLEBSICURE), powered by EUREKA and the European Community; the German Federal Ministry of Education and Research (H.W.); and the International Max Planck Research School for Infectious Diseases and Immunology (T.R.).

Gene sequence alignment of IGH and IGK or IGL variable regions of the indicated mutated mAbs and their inferred germline counterpart compared to the respective germline V and J gene segments. CDRs are highlighted.

a,b, Reactivity of the indicated mAbs with intestinal microbes of 31/41 tested human stool samples (a) and from a single individual as measured by flow cytometry compared to the PBS negative control (b). Sorting gate and percentage of antibody-bound bacteria are indicated. The K. pneumoniae O-serotype, S. cerevisiae, and gp140 reactivity profiles of each antibody are shown. Data are representative of two independent experiments (b).